This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ubiquitous beta-herpes virus CMV exhibits a number of natural adaptations, including 1) elicitation and long-term maintenance of uniquely strong (mucosally-oriented) cellular and humoral immunity, 2) lifelong persistence despite this robust immune response, 3) the ability to subclinically re-infect and immunologically boost fully immune hosts, and 4) little pathogenicity in normal hosts that make it a provocative candidate for development as a vaccine vector for chronic, elusive lentiviral pathogens like HIV/SIV (for which protection will likely require potent, long-lasting cellular and humoral immunity). The overall goal of this proposal is to use the rhesus macaque (RM) model (RhCMV/SIV) to explore the hypothesis that the special adaptations of CMV vectors (immunogenicity, persistence, ability to re-infect immune hosts) can quantitatively and/or qualitatively improve on the immunogenicity of current vaccine strategies, and as a result, safely elicit protective lentivirus-specific immunity. Work in the past year has confirmed the ability of CMV vectored, SIV-specific responses to provide early, high level protection against repeated limiting dose intra-rectal challenge with the highly pathogenic SIVmac239 virus.